Persistent viral infections are one of the greatest health concerns worldwide. With over 500 million people infected with HIV, hepatitis B and C viruses (HBV, HCV) the treatment of these infections represents a major challenge to medical science. Therapies to cure persistent viral infections have largely been unsuccessful because it is unclear exactly what is required of the immune system to purge virus once it proceeds past acute infection. In addition to CD8 T cells, mounting evidence indicates that CD4 T cell helper responses play a crucial role to sustain immune competence and that the loss of CD4 T cell functions is a key event permitting viral persistence. Interestingly, many of the functional characteristics of CD8 T cell exhaustion (failure to sustain activity, proliferate, develop memory) can potentially be explained by the loss of CD4 help. On the other hand, CD4 T cells can also produce factors that suppress immunity. Thus, the actual impact of the loss of CD4 T cell help on immune failure during persistent viral infection is largely unknown. The goal of this proposal is to determine the factors produced by CD4 T cells that suppress immunity during persistent viral infection and the mechanism(s) of CD4 T cell exhaustion. To achieve this goal I will investigate a novel role of IL-21 and the transcriptional repressor Blimp1 in suppressing T cell immunity, and specifically CD4 T cell helper activity, during viral persistence. I discovered these factors by gene-regulation analysis and selected them for study because they are dramatically over-expressed and have no previously known function during persistent viral infection. The experiments I propose will establish the interaction between IL-21 and Blimp1 and will define in vivo a novel host-derived transcriptional mechanism of T cell suppression during persistent viral infection. Additionally, these studies will provide the unique opportunity to investigate the functional impact of prolonged CD4 T cell help and therapeutic blockade of IL-21 to sustain /restore immunity during persistent viral infection. Once completed this effort will have a direct impact toward our understanding of host- virus interactions, the mechanisms employed to promote clearance versus persistence and therapeutically, the ability to restore immune function to purge persistent viral infections. [unreadable] [unreadable] [unreadable] [unreadable]